The present invention relates generally to riboflavin analogues which are competitive inhibitors of the enzyme flavokinase (EC 2.7.1.26). In one aspect the invention relates to a method for reducing blood pressure of a subject suffering from hypertension by administering to such subject an effective, non-toxic dosage of riboflavin analogues which are competitive inhibitors of the enzyme flavokinase. More specifically, but not by way of limitation, the present invention relates to the use of endo- and exocyclically substituted isoalloxazine derivatives as antihypertensive agents for reducing the blood pressure of a subject having hypertension.
It is generally known that expansion of body fluid volumes by renal retention of sodium results in an increase in the blood pressure of an individual. It is further known that certain riboflavin analogues function as competitive inhibitors of the enzyme flavokinase.
I have hertofore reported at the 60th Annual Meeting of the Endocrine Society, held at Miami Beach, Florida during June 14-16, 1978, in a paper entitled "Aldosterone Stimulation of Riboflavin Incorporation into Rat Renal Flavin Coenzymes and the Effect of Inhibition by Riboflavin Analogues on Sodium Reabsorption" and published in the Journal of Clinical Investigation, Volume 62, Number 6, 1325-1333, December 1978, that the administration of aldosterone to adrenalectomized male Sprague-Dawley rats significantly increased the biosynthesis of renal flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in the adrenalectomized male rats. It was further reported that aldosterone significantly decreased the excretion of sodium and increased the excretion of potassium. To determine if the increased biosynthesis of the flavin coenzymes were causing the alterations in urinary sodium and potassium output by aldosterone, the riboflavin analogues, 7,8-dimethyl-10-(2'-hydroxyethyl) isoalloxazine, and 7,8-dimethyl-10-formylmethyl isoalloxazine, were administered to the animals to diminish the conversion of the riboflavin to renal flavin mononucleotide (FMN) by competitively inhibiting the enzyme flavokinase.
The above identified riboflavin analogues, when administered in optimal doses of from about 10 micrograms/100 grams body weight to about 25 micrograms/100 grams body weight effectively opposed the diminished urinary excretion of sodium due to aldosterone. An inverse relationship was detected between the increase in urinary output of sodium and the decrease in renal flavin mononucleotide (FMN) when the animals were treated with aldosterone plus the riboflavin analogue as compared to treatment with the aldosterone alone. The riboflavin analogues reportedly exacted no significant effect on the increased excretion of potassium or on the enhanced synthesis of renal flavin adenine dinucleotide (FAD) by the aldosterone. Further, the analogues alone had no influence on the urinary sodium and potassium output and the renal flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) biosynthesis at the dose levels investigated. The conclusion thus reached was that the enhanced synthesis of renal flavin mononucleotide (FMN) may be a causative factor in the increased reabsorption of sodium due to aldosterone and that riboflavin analogues may be employed as a class of antimineralocorticoids.
However, no suggestion was made, nor has it heretofore been considered, that such riboflavin analogues possessed any other biological properties other than as antimineralocorticoids. Further, it is well recognized that excess sodium retention and hypertension are two distinct and separate pathophysicological processes of the human body and one does not necessarily give rise to the other. Thus, the treatment for sodium retention may not be the same as for hypertension and vice versa, and the antimineralocorticoids effective for depleting sodium from the body cannot be predicted as being effective anti-hypertensive agents.
The present invention is the result of original investigative research into the effects of antimineralocorticoids on hypertension, and an object of the present invention is to provide a method for reducing the blood pressure of an individual suffering from hypertension.
Another object of the invention is to provide a compound which, when administered to an individual having hypertension in a non-toxic dosage, effectively reduces the blood pressure of such individual without harmful side effects.
These and other objects, advantages and features of the present invention will be apparent to those skilled in the art from a reading of the following detailed description when read in conjunction with the drawings which accompany the disclosure and with the appended claims.